Overview The suprachiasmatic nucleus (SCN) serves as a circadian pacemaker that drives daily rhythms in vertebrate behavior and physiology. It generates robust, self-sustained oscillations that entrain to the local day-night cycle including hormone secretion, metabolism and sleep-wake. In addition, the SCN must adapt to slow seasonal changes in day length and, with travel across time zones, rapid shifts in the 24-h environment. It is an important and fundamental question how the oscillatory systems balance robust rhythmicity with flexible synchronization. Intellectual Merit: We hypothesize that opposing actions of two coupling agents contribute to the robust, yet sensitive, cycling of the network of SCN cells. Vasoactive intestinal peptide (VIP) and ?-aminobutyric acid (GABA) are key neurotransmitters involved in the generation and maintenance of SCN rhythms. Genetic and pharmacological experiments revealed central roles for VIP and its canonical receptor (VPAC2R) and GABA and GABAA receptors in synchronization among circadian cells. We will test the hypothesis that GABA signaling makes SCN timekeeping less precise but more amenable to phase shifting by external stimuli, such as light. We will combine theoretical and experimental tools to study the synergistic actions of VIP and GABA for synchronization among cells and entrainment to the environment. The SCN provides an outstanding model system of coupled oscillators that can be studied in vivo, reduced and simplified to a slice or individual cells in vitro, and modeled in silico. Although it is comprisedof thousands of heterogeneous cells, the SCN offers a unique opportunity to understand the balance between reliable rhythmicity and adaptable synchrony. We have three specific research aims: 1. Data-driven modeling of two competing coupling mechanisms. 2. Experimental studies of GABA blockade and enhancement in wild-type and VIP-deficient mice. 3. Theoretical and experimental optimization of adjustment to shift work via dosing strategies of benzodiazopines. Broader impacts The proposed research includes the development of novel software (the Entrainometer) for analysis of rhythm synchronization to a periodic input. This software will be freely available and useful to a wide range of scientists wanting to reliably measure features of entrainment. The proposal also includes significant outreach, education, and research opportunities. Both Drs. Herzog and Herzel are deeply committed to training young scientists. Dr. Herzog founded the St. Louis Chapter of the Society for Neuroscience through which he runs major outreach activities including NeuroDay (1500 visitors), HealthFest (1500 visitors) and the St. Louis Area Brain Bee (40 competitors, 200 participants). He also runs a 1-week summer course for high school teachers that includes material on circadian rhythms. Both Drs. Herzog and Herzel have taught in and directed the International Chronobiology Summer School for many years (including 2014 in Sapporo, Japan). As the 2014 Program Chair for the Society for Research on Biological Rhythms, Dr. Herzog promoted advocacy to the general public (e.g., a discussion of school start times) and chronobiology education (e.g. how to use chronobiology to excite students about physics, chemistry, math and biology). He continues to share his enthusiasm for rhythms research as the 2014-1016 Chair of Fundraising for SRBR. As part of this collaboration, the PIs will develop Modeling Circadian Clocks, a teaching module, for use by undergraduate and graduate educators around the world.